At the beginning of the 21st century, lung cancer continues to be the world's leading cause of preventable death. Lung cancer was a rare disease at the start of the past century, but the generalization of smoking made lung cancer one of the largest epidemics of the 20th century. By the early 1950s, case-control studies showed that cigarette smoking was causally associated with an increased risk of lung cancer, and this association was later corroborated by cohort studies. By 1964, the evidence was sufficient to support a conclusion by the US Surgeon General that cigarette smoking caused lung cancer. + more...

Lung cancer incidence rates showed marked sex differences in Spain. In men, incidence reached their peak during the late 1990s (with a maximum age-standardized incidence of 85 per 100 000 men in 1997 -99), and decreased thereafter. In women, however, incidence was on the rise. In Spain, lung cancer is the most common cause of cancer-related death. It accounted for almost 20,000 deaths in 2007. In men, lung cancer mortality is equivalent to that jointly caused by cancers of the colon, stomach, prostate, and bladder. From 2003 to 2007, lung cancer was still the malignancy causing the highest mortality among males (27.5%), followed by colorectal (12.9%) and prostate cancer (9.1%). Among females, colorectal cancer and breast cancer were the most frequent cause of cancer mortality (16.2%in both cases), followed by lung cancer (6.9%). Importantly, smoking-related cancer mortality is rising in recent years among Spanish females. Laryngeal and lung cancer increased from the mid-1990s, by 2.0% and 3.1% per annum, respectively. The lung cancer (and other major cancers) trends by sex and year are plotted in Figure. Lung cancer survival after diagnosis is poor. In Spain, as in other European countries, the lung 5-year survival rate does not exceed10% and show some differences according to age. In Spanish men, survival declined from 20% in the 15 -44 age group to 5% among those aged >74 years. W omen diagnosed with lung cancer at ages 15 -44 years had a lower survival than those diagnosed at ages 45 -64 years. Prognostic factors in lung cancer include presence or absence of pulmonary symptoms, tumor size, histology, stage. Cigarette smoking is the leading cause of lung cancer, accounting for approximately 90% of lung cancer cases in developed countries. Tobacco is the main risk factor for other upper respiratory tract cancers. In Spain (2006), 53,155 deaths were attributable to smoking, mainly due to lung cancer (16,482 deaths). Compared to never-smokers, smokers have about a 20-fold increase in lung cancer risk.

In the last five to ten years, several scientific, translational and clinical breakthrough shave occurred in the field of lung cancer. According to the results of the NCI sponsored CT-based early detection NLST trial, the prospect of a 20% reduction of lung cancer mortality may not be a wishful thinking anymore. The last decade has also seen a substantial advance in the understanding of non-small cell lung cancer biology. Some of the most striking examples of the therapeutic value and the survival advantage of molecular targeted therapies have happened recently in lung cancer trials (EGFR inhibitors, ALK inhibitors). The current whole sequencing efforts in NSCLC or SCLC specimens will very likely bring soon to the arena new candidate targeted pathways , and many more candidate drugs. Despite these promising results lung cancer (LC) is still the most lethal type of cancer worldwide. The extremely bad prognosis of LC patients is partly due to the late diagnosis of the disease, but also to the lack of effective therapies. Traditional treatment of pulmonary carcinomas is oriented towards surgery combined with classical chemotherapy in tumors at early stages (< 20% of the patients diagnosed), or towards classical chemotherapy and/or radiation therapy in advanced tumors. Chemotherapy is applied with the majority of patients, but it so far has only improved survival in very small cohorts. In spite of our rapidly growing understanding of the epigenetic and genetic profile of LC, the knowledge has barely been used to improve therapeutics. One of the few exceptions which exemplifies the impact of understanding tumor genetics is the test for EGFR mutations, currently used in the clinic in order to distinguish those lung adenocarcinoma patients, preferably non-smokers, who will respond to treatment with specific EGFR tyrosine kinase inhibitors (erlotinib, gefitinib).

Progress beyond the plateau, which has been reached in the treatment of LC with current drugs, mainly depends on two aspects: the discovery and validation of potential novel drugs targeting specific tumor-molecular alterations and the understanding of the biological factors determining drug sensitivity and intrinsic (primary) and acquired resistance. In parallel, novel high throughput technologies now enable scientists to use state-of-the-art methods allowing the study of global patterns of molecular alterations in cancer cells and in clinical patient materials. Novel preclinical developments, including animal and cellular tumor models of various types (e.g. transgenic mice, knockout mice, stable and inducible transfection of genes into cancer cells), the emerging science of tumor stem cells, and novel techniques such as RNA interference allowing specific targeting of key genes as well as in depth genome wide sequencing on state of art platforms (HiScan-Illumima) are prime examples of potentially important advances. Combined with the fast progress in cell biology and molecular genetics, the possibilities of using these technologies in order to identify critical ?drugable?molecules for cancer therapy and of getting a more profound understanding of molecular mechanisms underlying the tumor cell response to a given drug have become much more favourable.

Nevertheless, major challenges are still ahead in order to solve or alleviate the crucial problems affecting lung cancer patients, their families and the Public Health System of every country. Our understanding of lung cancer has never been deeper. Yet there is so much more to be learned. Some of these urgent needs are addressed in the workplan our Programme which is described in the following paragraphs of this section.

The scientific main goals of our proposal are to understand the biological intricacies of the disease in order to develop diagnostic, prognostic or predictive markers and more successful therapies. We are also determined to optimize preventive strategies in lung cancer. To achieve these goals we have developed a work plan which includes 6 workpackages (WPs).

TThe lung and upper respiratory tract cancer program is composed of 14 research groups. They include the most active groups clinical and translational research groups in Spain in the field of Lung and Head and Neck cancer, according to their recent (5 years) publications record, grant support and international recognition. The programme has an optimal balance between Basic and Clinical-Epidemiological Research groups (5 vs 9 respectively), and all the groups are active in translational research projects. Figure shows a summary of the groups included in our programme together with their institutions and their general expertise: Dr. Luis Montuenga (group 2) will be the coordinator of the programme.

Multidisciplinarity is a strong asset in our programme, which includes investigators with all the necessary expertise to successfully achieve ambitious scientific goals in lung and upper respiratory tract cancer research, namely: Cell and Molecular Biologists, Medical Chemists, Pathologists, Clinical Oncologists, Surgeons, Epidemiologists, Pulmonologists,etc. Synergies between the different specialities are completely mandatory to solve the challenging questions which lung cancer research is facing. Most of the groups within our programme are already multidisciplinary and are used to foster transdisciplinary collaborations and synergies, due to their strong involvement in translational research. The RTICC programme that we are describing is an excellent opportunity to further these multidisciplinary synergies to a new level of achievements. W e are covering all the different backgrounds and skills needed for a really integrative approach between groups within each of the main work packages and among the workpackages.

Most of the groups are involved in more than one workpackage. This multiple workpackage involvement will facilitate the transversal collaborations within the programmes. Some of the groups will also collaborate with at least one workpackage included in other programmes, which also helps in the cohesion and integration of the whole RTICC network. The different approaches of the 6 workpackages, included in the lung cancer programme, from the basic molecular analysis of carcinogenesis to the broad epidemiological focus on lung cancer prevention through screening of high risk populations, may result in many interesting cross-fertilization between different perspectives. Finally, past cooperative experience between many of the groups in the previous RTICC provides a further reassurance that the future prospect of increased synergy will continue to take place.

Finally, in order to assure that every necessary expertise is at hand at every moment, it will be imperative to put specific collaborative agreements with external institutions also interested in lung and upper respiratory tract research in place to define a successful synergistic framework. In particular, we have proposed a specific collaboration agreement with CIBERES, a multidisciplinary and multi-institutional research network in respiratory diseases supported by the Carlos III National Institute of Health. W e will also propose a collaborative agreement with the Spanish lung cancer group(SLCG), internationally well known by its involvement in a large number of seminal clinical trials that have paved the way to many successful clinical therapeutic innovations. The present leadership and key investigators of SLCG are Principal Investigators of our present proposal.

The number of groups included in the programme (14 groups) is much larger than the minimum (6 groups) required by the call. This number is adequate to carry out the 6 workpackages proposed, especially considering the involvement of groups in more than two (often three) workpackages. The size and scientific excellence indicators of each of the groups clearly show that the necessary critical mass is present in our Programme. Most of the groups include a much larger number of senior scientists than the minimum required by the grant call (minimum of 4 staff scientists). We also have the necessary critical mass of the different specialties. For example, we include the most recognized 4 lung pathologists in Spain, which are very necessary to achieve several of the scientific aims successfully. We include the two Spanish scientists who have published about lung cancer screening more extensively. We include the most renowned specialists in smoking prevention, and the most internationally recognized Spanish lung cancer Clinical Oncologists.

The coordinator of the Programme is Dr. Luis M. Montuenga. Also, the coordinator of the programme will be member of the executive board of the RTICC. The IP of each group will be part of the Executive Board of the Programme. W e will recommend to the IPs of the 6 groups funded by other programmes to delegate his representation to the Lung Cancer Programme to the member of their groups more directly involved in the workpackages. Considering the background of the PIs present in the Programme, the Executive Board of the Programme will include different specialties (five PIs are molecular biologists, six PIs are clinical oncologists, one PI is a lung specialist, one is a surgeon, and one is an epidemiologist).

The WP leaders will support the management through the coordination of the different researchers involved in each WP and will report periodically to the Executive Board. The coordinator will supervise the different W P activities. The executive board will meet regularly (at least every two months) in person or through teleconference. A general review of the activities will be performed annually by the Executive Committee of the Programme. All the scientists involved in the Programme will gather together at the yearly scientific meeting of the Programme. Considering the number of groups, the past experience in cooperation among themselves as well as the workplan, this structure is considered sufficiently easy to manage.

Each of the partners adds specific value to the consortium. Dr. Rosell has extensive experience in clinical trials and predictive Biomarkers, is the founding leader and President of the Spanish Lung Cancer Group, and has a very experienced laboratory in the field of molecular profiling of lung cancer patients. Dr. Montuenga provides experience in Cellular and molecular carcinogenesis, animal models and translational research in early lung cancer. He, together with Dr. Zulueta, has built an extensive biobank of high-risk individuals and early tumors with tight SOPs and long follow up. Dr. Sanchez Cespedes is an internationally recognized scholar in the field of lung cancer genetics and has the required molecular expertise to lead W P1. Dr. Esteller is also a world renowned expert in epigenetics, and has a special interest on Epigenetic prognostic and predictive markers in lung cancer. Dr. Camps has a translational research lab mainly interested in pathways related to angiogenesis. Together with Dr. Luis Paz-Ares, they are also an active part of SLCG. Dr. Paz Ares´ group has made a great effort in developing either genomic and proteomic strategies to approach Molecular and genetic profiling of stage I NSCLC and early detection biomarkers. In addition they have studied different biological markers for staging, Prognostic markers and Molecular and genetic specific differential profiling of different histological types of lung carcinoma. He has joined forces with Dr. Amancio Carnero, who leads a lab focused on new therapeutic drugs. Dr. Carnero has published extensively in this field and has a specific interest in blocking oncogenic pathways in lung cancer. Dr. Lacal´s group has also been engaged in the identification of potential molecular targets for the design of novel therapeutic strategies against cancer. Dr. Paramio is an expert in squamous tumors and has developed numerous genetic engineered mouse models (GEMMs) of squamous differentiated tumors that are now being used for preclinical analysis of potential antitumoral drugs. Dr. Suarez is also expert in squamous Head and Neck cancers from the translational and clinical (surgical) point of view. For example, the group has established the first reported cell lines in sinonasal adenocarcinoma and squamous cell carcinoma of the sinonasal area and developed orthotopic mouse models that reproduce the molecular and pathological characteristics of head and neck tumors in humans. We also include a in expert in translational research in Small Cell Lung Cancer (Dr. Arriola in Dr. Albanell’s group), as well as the leading Spanish expert in screening for lung cancer, Dr. Zulueta, who will work together with Drs. Borras and Montuenga to develop a pilot feasibility programme of lung cancer screening. Finally, Dr, Melero (in Dr. Prosper’s lab) is in the forefront of immunotherapy research in solid tumors, both at the animal model level as well as in clinical trials.

Finally, the international networking ability of our programme is outstanding. Many of the PIs and researchers are members or the International Association for the Study of Lung Cancer (IASLC) and are currently or have been in the past members of the different committees of the association. Some are also involved as associate editors in several of the leading journals in the field (JTO, Lung Cancer, etc). Some of the groups are also part of the European Thoracic Oncology Platform (ETOP) and have active collaborations and joint publications with the key groups in the USA working on lung or upper respiratory tract tumors.

We want to focus and foster this synergistic work towards the resolution of a number of very ambitious scientific goals which have two main characteristics in common: a) they are clear and well defined urgent unmet medical needs in the field of lung and upper respiratory tract cancer; and b) they cannot be accomplished at the single-group level but require to be addressed through multi institutional and multidisciplinary collaboration.

The following are some examples of potential impact on urgent questions that lung and Head and Neck cancer scientists and clinicians are currently facing: (1) Better understanding of the genetic or epigenetic mechanisms that drive cancer progression; (2) Learning the molecular mechanisms that underlie clonal selection and allow the tumor cells to acquire their invasive potential; (3) Biological profiling and classification of lung or upper respiratory tract cancers; (4) Design of new and more successful targeted therapies to treat, not only advanced metastatic patients, but also earlier cases; (5) Design of new treatments which, not only improve patient symptoms and prolong progression free survival but, most importantly, significantly prolong overall survival; (6) Better understanding on how to block acquired resistance to conventional or molecular targeted treatments, a major concern and a serious drawback for every treatment developed in lung cancer; (7) Better knowledge about the genetic and phenotypic risks markers which associate to higher susceptibility to lung cancer; (8) Design of new minimally invasive lung cancer diagnostic techniques; (9) Exploration of new management strategies for very early tumors.

Along with high impact publications we expect some other technological contributions such as patents of biomarkers use for early detection of lung cancer or prediction of response, patents on new targets and new applications of compounds. Also we expect to propose some new clinical trials based on our discoveries. Furthermore we expect some no so clearly evaluable outputs such as new and improved management of lung cancer patients and new guidelines for clinical practice. W e expect also generate preclinical tools to better validate chemotherapy in lung cancer.

Several of the groups have long standing experience in technology transfer and clinical application of laboratory discoveries. A total of 17 patents have been filed by the groups in the last 5 years. Several of the partners have experience in direct involvement in collaboration with industry both at the discovery level and through participation in phase I-III trials. The intellectual property issues that may be related to collaborative projects will be dealt and discussed when necessary at the Executive Board meetings. Dissemination of this research will be made through the classical strategies based on papers published in the international literature, either in high impact general cancer or in cancer biology journals. Also, researchers of this programme are usually very active with presentations in national and international meetings. Thus it is foreseen that the results of the collaborative projects of the present programme will be disseminated readily at scientific meetings, both international and national.

The scheme of evaluation of this programme is based on two set of indicators: Indicators of the progress of the Programme and Indicators of performance of the groups. Long-term outcomes are not considered here because of the proposed four-year plan of funding of the RTICC, which clearly limit significantly the feasibility of outcomes beyond that timeframe. In order to reduce the administrative burden of this kind of necessary variables, the indicators of progress of the Programme are limited to three, quite simple to measure and easy to review by external advisors. Regarding the group indicators, the main set of indicators are papers published in cooperation with two or more groups of the RTICC and grants in competitive applications, also with the involvement of researchers of two or more groups of the program or other programs of this RTICC. Participation in join clinical trials will also be considered. These indicators are based on the deliverables of the cooperative projects described in the work plan. Other simple, and easy to measure additional indicators will be requested. As for the time-frame, we suggest evaluation in Year 2 and 4.

Indicators of the progress of the Programme:

Annual meeting of the Executive Board. Annual Report of the review of the objectives (see below) and research priorities, submitted by the coordinator of the programme.

Participation of researchers of the Program on Lung Cancer and Upper Respiratory Tract in other programs of the RTICC, measured in terms of WP collaborations, publications in collaboration and research grants. Report submitted by the coordinator of the programme.

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Severe infections after single umbilical cord blood transplantation in adults with or without the co-infusion of CD34(+) cells from a third-party donor: results of a multicenter study from the Grupo Español de Trasplante Hematopoyético (GETH).